Examination of signalling pathways involved in muscarinic responses in bovine ciliary muscle using YM-254890, an inhibitor of the Gq/11 protein.

BACKGROUND AND PURPOSE: In the ciliary muscle, the tonic component of the contraction produced by cholinergic agonists is highly dependent on Ca2+ provided by influx through non-selective cation channels (NSCCs) opened by stimulation of M3 muscarinic receptors. We examined effects of YM-254890 (YM), a Gq/11-specific inhibitor, on contraction, NSCC currents and [Ca2+]i elevation induced by carbachol (CCh). EXPERIMENTAL APPROACH: Isometric tension was recorded from ciliary muscle bundles excised from bovine eyes. In ciliary myocytes dispersed with collagenase and cultured for 1-5 days, whole-cell currents were recorded by voltage clamp and the intracellular free Ca2+ concentration [Ca2+]i was monitored using the Fluo-4 fluorophore. Existence and localization of M3 receptors and the alpha subunit of Gq/11 (Galpha(q/11)) were examined by immunofluorescence microscopy using AlexaFluor-conjugated antibodies. KEY RESULTS: Both phasic and tonic components of contractions evoked by 2 microM CCh were inhibited by YM (3-10 microM) in a dose-dependent manner. In the cultured cells, CCh (0.05-10 microM) evoked an NSCC current as well as an elevation of the [Ca2+]i. Both initial and sustained phases of these CCh-evoked responses were abolished by YM (3-10 microM). Immunostaining of the cytoplasmic side of the plasma membrane of ciliary myocytes revealed a dense distribution of M3 receptors and Galpha(q/11). CONCLUSIONS AND IMPLICATIONS: The tonic as well as phasic component of the ciliary muscle contraction appears to be under control of signals conveyed by a G(q/11)-coupled pathway. YM is a useful tool to assess whether Gq/11 is involved in a signal transduction system.

Agonist and antagonist sensitivity of non-selective cation channel currents evoked by muscarinic receptor stimulation in bovine ciliary muscle cells.

1 In the bovine ciliary muscle, stimulation of muscarinic receptors with carbachol (CCh) opens two types of non-selective cation channels (NSCCS and NSCCL) with widely different unitary conductances (100 fS and 35 pS). Here we examined the dependence of the activity of NSCCS on the agonist (CCh) concentration by whole-cell voltage clamp in freshly isolated bovine ciliary muscle cells. We also examined the sensitivity of CCh-evoked NSCCS currents to several muscarinic receptor antagonists. 2 The voltage clamp experiments were carried out using Ba2+ as the charge carrier, as this divalent cation is the most permeant for NSCCS of the alkali and alkaline earth metal ions hitherto examined, whereas it is relatively impermeant to NSCCL. For the dose-activation relationship obtained, the apparent dissociation constant K was estimated to be 0.5 +/- 0.2 microm (n = 31), a value of an order of magnitude smaller than the one reported for CCh-evoked NSCCL currents in our previous experiments. 3 In the dose-inhibition experiments we observed that the CCh-evoked NSCCS currents were inhibited by the muscarinic antagonists with the following potency sequence: atropine approximately 4-DAMP >> pirenzepine > AF-DX116, indicating that the activation of NSCCS by CCh is mediated by an M3 muscarinic receptor. 4 We have previously shown by reverse transcriptase-polymerase chain reaction that the bovine ciliary muscle contains mRNAs for several transient receptor potential channel homologues (TRPC1, TRPC3, TRPC4 and TRPC6) which are attracting attention as molecular candidates for receptor-operated NSCCs. In the present experiments, we succeeded in visually identifying these TRPCs in the plasma membrane of cultured bovine ciliary muscle cells by immunofluorescence microscopy.

Studies of alcohol-induced interdigitated gel phase in phosphatidylcholine multilamellar vesicles by the excimer method.

We have developed a new spectroscopic method (excimer method) for detecting the interdigitated gel phase (L beta I) in phospholipid vesicles. This method is based on the disappearance of an excimer fluorescence peak of pyrenephosphatidylcholine (pyrene-PC) in the L beta I phase. Using this method we have studied the phase transition from gel phase (L beta') to L beta I phase of dipalmitoylphosphatidylcholine multilamellar vesicles in the presence of ethanol or ethylene glycol (EG). In both the cases of ethanol and EG, a sharp decrease in the ratio of excimer to monomer fluorescence intensity (E/M) of pyrene PC appeared at the same concentration of the transition from L beta' to L beta I as determined by the X-ray diffraction method or the scanning density method. After the transition to the L beta I phase, E/M values became very low. This excimer method enables us to detect the L beta I phase in unilamellar vesicles of phospholipids, which can hardly be studied by other methods such as X-ray diffraction.

Effect of oligomers of ethylene glycol on thermotropic phase transition of dipalmitoylphosphatidylcholine multilamellar vesicles.

The effect of oligomers of ethylene glycol (EG) on thermotropic phase transitions of dipalmitoylglycerophosphatidylcholine multilamellar vesicles (DPPC-MLV) were investigated. Diethylene glycol (di-EG) had a biphasic effect on transition temperature, reducing pre-transition temperature (Tp) at low concentrations but increasing main transition temperature (Tm) and extinguishing pre-transition at high concentration. Results of the X-ray diffraction method and the excimer method indicated that di-EG induced interdigitated gel phase (L beta 1 phase) in the DPPC membranes at high concentration. Phase diagram of temperature-di-EG concentration for DPPC-MLV was determined by use of X-ray diffraction and differential scanning calorimetry, which was similar to that of temperature-EG concentration. The minimum concentration of di-EG where L beta 1 phase was induced was 42%(w/v), which was larger than that of EG (30%(w/v)). On the other hand, in the presence of triethylene glycol (tri-EG), Tm and Tp increased with an increased in tri-EG concentration, as well as poly(ethylene glycol). These differences, between the effects of di-EG and those of tri-EG, might be due to the differences of their sizes.

Efficacy of an enteral feeding protocol for providing nutritional support after paediatric cardiac surgery.

Enteral nutrition (EN) is considered to be a more appropriate method than parenteral feeding for providing nutrition to critically ill children. However, children who undergo cardiac surgery are at high risk of postoperative gastrointestinal complications during EN. The purpose of this study was to demonstrate the safety and efficacy of our EN feeding protocol after paediatric cardiac surgery through comparison between a single-centre prospective case series and historical cases. Forty-seven children who were admitted to the ICU after cardiac surgery were enrolled ('post group'). Data for these children were compared with a similar cohort of children who were admitted before the implementation of the feeding protocol (n=62; 'pre group'). The incidence of complications including vomiting, necrotising enterocolitis and hypoglycaemia; the time until the initiation of EN; and the changes in calories provided were compared between the groups. The frequency of vomiting was significantly lower in the post group than in the pre group (36.2% versus 58.0%, P=0.038), and necrotising enterocolitis did not occur in either group. The time until the initiation of EN and the total calories provided did not differ significantly; however, in the post group the proportion of energy provided by parenteral nutrition was significantly smaller (P <0.001), and provided by EN was significantly larger (P=0.003), than in the pre group. The frequency of hypoglycaemia was similar in both groups. This study showed that our EN protocol resulted in adjustments to calories provided via EN versus parenteral nutrition after paediatric cardiac surgery, and reduced the frequency of vomiting.

[Pharmacokinetic, bacteriological and clinical evaluation of tazobactam/piperacillin in pediatrics].

Pharmacokinetic, bacteriological and clinical studies were performed in pediatrics on tazobactam/piperacillin (TAZ/PIPC), a combined drug of a new beta-lactamase inhibitor tazobactam and piperacillin at a ratio of 1:4. 1. Serum levels and urinary excretions of TAZ, PIPC and desethyl piperacillin (DEt-PIPC), a metabolite of PIPC, after one shot intravenous administration of 50 mg/kg of TAZ/PIPC to two children (6-7 years old) were investigated. The serum TAZ level at 0.08 hour was 50.8-51.0 micrograms/ml after administration. Then TAZ concentrations gradually decreased with half-lives of 0.38-0.45 hour, and reached 1.0-1.4 micrograms/ml after 2 hours and was not detected after 3 hours and 6 hours. Serum PIPC levels at 0.08 hour was 167.0-231.0 micrograms/ml after administration. Then PIPC concentrations gradually decreased with half-lives of 0.41-0.55 hour, and reached 1.2-2.4 micrograms/ml after 3 hours and was not detected after 6 hours. DEt-PIPC was detected slightly in serum. A ratio of TAZ to PIPC was about 1 to 4 in serum at each time. Urinary recovery rates of TAZ in the first 6 hours after administration of TAZ/PIPC were 33.5-90.1% and those of PIPC were 41.9-77.8% and those of DEt-PIPC were 1.5-2.8%. 2. TAZ/PIPC was administered to 27 pediatric patients (their ages ranged between 2 months and 11 years old) with various infections, and clinical and bacteriological effects and adverse reactions were investigated. Single doses were 26.2-55.6 mg/kg, frequencies of administration were 3-4 times a day, and durations of administration were 3 1/3-7 1/3 days, and total dosages were 4.5-33.75 g. Clinical effects were evaluable in 26 cases. Responses were rated as "good" in acute purulent tonsillitis 1 case and acute purulent otitis media 1 case, as "excellent" in acute sinusitis 1 case, as "excellent" in 2 and "good" in 1 out of 3 cases of acute bronchitis, as "excellent" in 13 and "good" 2 out of 15 cases of acute pneumonia, as "excellent" in acute urinary tract infection 2 cases and as "excellent" in acute enteritis in 1 case, acute appendicitis in 1 case and lymphadentis in 1 case. In all cases, the results were rated as "good" or "excellent". Antimicrobial effects against a total of 10 strains identified or assumed to be pathogenic bacteria were evaluated. The 10 strains of bacteria included 4 strains of Streptococcus pneumoniae, 3 strains of Haemophilus influenzae (2 strains beta-lactamase producing), 2 strains of beta-lactamase producing Moraxella catarrhalis, 1 strain of beta-lactamase producing Morganella morganii. All the bacteria listed here were judged to have been eradicated. Adverse reaction was observed in 1 case with mild diarrhea. As abnormal changes in laboratory data, leucocytopenia in 1 case, elevation of GOT. GPT in 2 cases and eosinophilia in 1 case were observed. On the basis of the findings, TAZ/PIPC was considered to be effective and safe in the treatment of pediatric infections.

[Clinical study on cefprozil in pediatrics].

Clinical efficacy and safety of cefprozil (CFPZ, BMY-28100), a newly developed oral cephalosporin, were studied in our pediatric department. Clinical effectiveness, bacteriological effectiveness and side effects were studied in 116 pediatric patients with ages ranging 4 months to 11 years. CFPZ was given 4.6-14.1 mg/kg daily in 3 times for 3-10 days. Clinical efficacies were evaluated in 112 patients, and the therapeutic effectiveness were excellent in 1 and good in 6 for 7 patients with acute pharyngitis, excellent in 24 and good in 26 for acute purulent tonsillitis, excellent in 3, good in 8 and fair in 1 for acute bronchitis, excellent in 21, good in 7, fair in 1 and poor in 1 for acute pneumonia, excellent in 1 acute purulent parotitis, excellent in 2 and good in 7 for acute UTI, good in 1 impetigo, fair in 1 periproctal abscess and good in 1 acute enteritis. The effectiveness rate was 96.4%. Bacteriologically, 4 strains of Staphylococcus aureus (beta-lactamase producing strains), 1 strain of Staphylococcus epidermidis (beta-lactamase producing strain), 2 strains of Streptococcus pneumoniae, 2 strains of Streptococcus agalactiae, 4 strains of beta-Streptococcus, 1 strain of Klebsiella pneumoniae (beta-lactamase producing strain) and 1 strain of Salmonella C2 were all disappeared, and of 22 strains of Streptococcus pyogenes, 20 strains were disappeared, 1 was decreased and 1 was unknown, of 5 strains of Escherichia coli (3 beta-lactamase producing strains), 4 were disappeared and 1 was decreased, of 29 strains of Haemophilus influenzae (14 beta-lactamase producing strains), 14 were disappeared, 11 were decreased, 3 persisted and 1 was unknown and of 2 strains of Haemophilus parainfluenzae (1 beta-lactamase producing strain), 1 was disappeared and 1 persisted. The bacteriological eradication rates for Gram-positive bacteria and Gram-negative bacteria were 97.1% and 56.8%, respectively, and the drug was especially effective against Gram-positive bacteria. No side effects nor refusal of ingestion were observed. As abnormalities in laboratory test results, 3 cases of elevation of eosinophil counts and 1 of elevation of platelet counts were observed. In conclusion, CFPZ was considered to be a safe and highly effective antibiotic in pediatric infections.

[Laboratory and clinical studies on cefadroxil in the field of pediatrics (author's transl)].

Laboratory and clinical investigations were performed in the field of pediatrics with cefadroxil dry syrup, a new semi-synthetic cephalosporin antibiotic. (1) MIC of cefadroxil was measured, to compare with that of cephalexin (CEX), on 30 strains of S. aureus, 30 strains of S. pyogenes and 26 strains of E. coli, all of which were isolated clinically in the field of pediatrics. Two strains of S. aureus showed more than 100 microgram/ml with inoculum size of 10(8) cells/ml, and remaining 28 strains were distributed between 1.56 similar to or approximately 12.5 microgram/ml, while at inoculum size of 10(6) cells/ml, each 1 strain showed 25 microgram/ml and 50 microgram/ml, and the remaining strains were distributed between 1.56 similar to or approximately 3.13 microgram/ml. All 30 strains of S. pyogenes were inhibited the growth by less than 0.2 microgram/ml with inoculum size of both 10(8) cells/ml and 10(6) cells/ml. Three strains of E. coli showed MIC of more than 100 microgram/ml with inoculum size of 10(8) cells/ml, and the remaining 23 strains were distributed between 12.5 similar to or approximately 25 microgram/ml, while with inoculum size of 10(6) cells/ml, 3 strains showed more than 100 microgram/ml, and the remaining strains were distributed between 6.25 similar to or approximately 12.5 microgram/ml. In comparison with the results of CEX, cefadroxil was nearly equal to S. aureus and E. coli, whereas it was 2 grades superior to S. pyogenes. (2) A dose of 10 mg/kg of cefadroxil dry syrup was administered before 30 minutes of breakfast in 3 cases of children, and serum level, urinary level and recovery rate in urine were investigated. Average serum level was 15.2 +/- 2.39 microgram/ml in 1/2 hour, 16.4 +/- 2.3 microgram/ml in 1 hours. 10.1 +/- 2.8 microgram/ml in 2 hours, 3.8 +/- 1.5 microgram/ml in 4 hours and 1.0 +/- 0.4 microgram/ml in 6 hours, and average T 1/2 was 1.24 +/- 0.22 hours. Average urinary level was 857 +/0 232 microgram/ml in 0 similar to or approximately 2 hours, 690 +/- 180 microgram/ml in 2 similar to or approximately 4 hours and 249 +/- 55 microgram/ml in 4 similar to or approximately 6 hours, and average recovery ratio in urine was 86.3 +/- 17.5% within 0 similar to or approximately 6 hours. (3) Cefadroxil dry syrup was administered clinically in 20 cases of acute purulent tonsillitis, 5 cases of acute bronchitis, 14 cases of acute pharyngitis, 5 cases of acute purulent cervical lymphadenitis and 2 cases of acute urinary tract infection. Clinical efficacy, bacteriological effect and its side effect were investigated in total 46 cases of bacterial infection. A dose of 21.1 similar to or approximately 57.1 mg/kg of cefadroxil was administered daily, divided into 3, after each meal for 1 similar to or approximately 10 days, total dose being 0.5 similar to or approximately 11.0 g. Efficacy rate of cefadroxil, including excellent and effective effects, was 90.0% in acute purulent tonsillitis, 60.0% in acute bronchitis, 100.0% in acute pharyngitis, 80...

[A study of the absorption and excretion of fosfomycin sodium in children].

Fosfomycin sodium (FOM-Na, Forocyle-S) was administered at 25 mg/kg or 50 mg/kg to 15 children between the ages of 3 and 15 through intravenous injection or through 1 hour intravenous drip infusion, and concentrations in blood serum and excretion through urine were examined and a pharmacokinetic analysis was carried out using the one-compartment model. 1. Average concentrations in the blood serum after injections with 25 mg/kg and 50 mg/kg were 55.3 +/- 6.3 micrograms/ml and 118.8 +/- 31.1 micrograms/kg 30 minutes after injection, respectively, and their half-lives were 1.04 +/- 0.15 hours and 0.98 +/- 0.17 hours, respectively. Six hours after injection, the levels were 2.7 +/- 1.6 micrograms/kg and 6.2 +/- 5.5 micrograms/kg, respectively. With 1 hour intravenous drip infusion of 25 mg/kg and 50 mg/kg, average concentrations the blood serum were 34.2 +/- 14.9 micrograms/ml and 89.7 +/- 6.7 micrograms/ml, respectively, and their half-lives were 0.87 +/- 0.24 hour and 0.69 +/- 0.10 hour, respectively. Six hours after the administration, the levels were 2.7 +/- 1.8 micrograms/ml and 6.7 +/- 0.8 micrograms/ml. There was a clear dose response in the concentration levels in the blood in those given the drug at 25 mg/kg and 50 mg/kg in either method of administration. 2. Average levels in urine after injection of 25 mg/kg and 50 mg/kg were 5,778 +/- 2,257 micrograms/ml and 6,268 +/- 3,329 micrograms/ml 0-2 hours after administration, respectively, and average levels at 4-6 hours were 701 +/- 765 micrograms/ml and 1,588 +/- 1,324 micrograms/ml, respectively. Average excretion, rates into the urine were 72.8 +/- 11.0 and 73.9 +/- 11.1%, respectively. In case of 1 hour drips infusion of 25 mg/kg and 50 mg/kg, average concentrations in the urine 0-2 hours after administration were 3,570 +/- 1,540 micrograms/ml and 11,800 micrograms/ml, respectively, and averages for 4-6 hours were 211 +/- 124 micrograms/ml and 1,300 micrograms/ml. Average rates of excretion into the urine for the first group was 57.9 +/- 16.3% and the second group was 78.4%. Clear dose response was observed in changes of drug concentration levels in the urine with 25 mg/kg and 50 mg/kg doses through either administration method, and in terms of excretion into the urine, no noticeable differences were observed between the different amounts administered or different administration methods.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetic, bacteriological and clinical evaluations of cefdinir 10% fine granules in pediatrics].

Pharmacokinetic, bacteriological, and clinical studies on cefdinir (CFDN, FK482) (10% fine granules), a new oral cephem, were performed in pediatrics. 1. Bioequivalencies of plasma concentrations and urinary excretions of CFDN 5% and 10% fine granules were investigated on 3 pediatric patients with ages between 5 to 13 years administered with a drug in fasting state at a dose level of 3 mg/kg using a cross over method. Average plasma concentrations in a group of patients administered with 5% fine granules peaked at 3 hours after administration with a level of 1.05 +/- 0.29 micrograms/ml (mean +/- S.E.) and decreased to 0.12 +/- 0.05 micrograms/ml at 8 hours with a half-life of 1.48 +/- 0.09 hours. In the group administered with 10% fine granules, average plasma concentrations peaked at 2 hours after administration with a level of 1.32 +/- 0.12 micrograms/ml, and decreased to 0.20 +/- 0.11 microgram/ml at 8 hours with a half-life of 1.68 +/- 0.28 hours. The first 8-hour urinary recovery rates of CFDN in the 5% and 10% fine granules groups averaged 19.64 +/- 5.69% and 23.37 +/- 2.36%, respectively. Both average and individual plasma concentrations and urinary recovery rates in the patients of the 10% fine granules group were somewhat higher than those of the 5% fine granules group, but no significant differences were observed between the 2 groups including areas under concentrations. 2. CFDN 10% fine granule preparation was administered to 33 pediatric patients with ages between 1 to 13 years with various infections, and its clinical effects, bacteriological effects and safety were assessed. In 31 of the 33 patients (2 patients were excluded since they were with non-bacterial infections) clinical effects were excellent in all of 9 patients with scarlet fever (3), acute pharyngitis (3) or impetigo (3), excellent in 12 and good in 3 of 15 patients with acute purulent tonsillitis, and excellent in 4 and good in 3 of 7 patients with acute pneumonia. The overall efficacy rate was 100%. Bacteriological effects against causative organisms were evaluated. All the identified Staphylococcus aureus (4 strains) and Streptococcus agalactiae (1) were eradicated. Of 10 strains of Streptococcus pyogenes, 9 strains were eradicated and the other one was reduced. Of 7 strains of Haemophilus influenzae 4 were eradicated, 1 persisted and the fate of the remaining 2 were unknown. The overall eradication rate was 90.0%. Microbial substitutions were observed in 5 patients. The new, replacing bacteria were all Haemophilus spp.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetic, bacteriological and clinical evaluation of cefditoren pivoxil in pediatrics].

Pharmacokinetic, bacteriological, and clinical studies were performed in pediatrics on cefditoren pivoxil (CDTR-PI, ME1207) in granules. 1. Serum concentrations and urinary excretions of CDTR after administration of CDTR-PI to children (ages between 1 and 10) were investigated. Five cases were administrated with CDTR-PI at a dose level of 3 mg/kg 30 minutes after meal. Serum concentrations in these cases reached their peaks at 2 hours after administration with an average level of 1.23 +/- 0.34 micrograms/ml and diminished to 0.04 +/- 0.04 micrograms/ml at 8 hours after administration with a half-life of 1.60 +/- 0.38 hours. Urinary recovery rates of CDTR in the first 8 hours after administration of CDTR-PI averaged 14.9 +/- 0.9%. Five cases were administered with CDTR-PI at a dose level of 6 mg/kg 30 minutes after meal. Serum concentrations with the drug after meal reached their peaks at 1 hour after administration with an average level of 2.62 +/- 0.42 micrograms/ml and diminished to 0.21 +/- 0.11 micrograms/ml at 8 hours after administration with a half-life of 1.58 +/- 0.31 hours. Urinary recovery rates of CDTR in the first 8 hours after administration of CDTR-PI averaged 17.0 +/- 0.7%. These data also showed that serum and urinary concentrations of the drug depended on dose levels. 2. CDTR-PI was administered to 31 pediatric patients (their ages ranged between 1 year and 10 years) with various infections, and clinical and bacteriological effects and adverse reactions were investigated. Clinical effects were evaluable in 24 cases including 2 cases of scarlet fever, 1 case of acute pharyngitis, 12 cases of acute purulent tonsillitis, 4 cases of acute bronchitis, 5 cases of acute pneumonia. Clinical responses were excellent in 16 cases, effective in 8 cases, with an efficacy rate of 100%. Antimicrobial effects against a total of 16 strains identified or assumed to be pathogenic bacteria were evaluated. The 16 strains of bacteria included 4 strains of Staphylococcus aureus, 6 strains of Streptococcus pyogenes, 2 strains of beta-Streptococcus, 4 strains of Haemophilus influenzae. All the bacteria listed here were judged to have been eradicated except 2 strains of H. influenzae (1 was decreased and 1 was unchanged) thus, the eradication rate was 87.5%. Two strains of bacteria replaced infection causing bacteria. Streptococcus pneumoniae replaced S. pyogenes and S. aureus replaced H. influenzae. No adverse side reactions were observed.(ABSTRACT TRUNCATED AT 400 WORDS)

[Laboratory and clinical evaluation of S-1108 in pediatric field].

We performed laboratory and clinical evaluation of S-1108 granules, a new oral cephalosporin antibiotic, in the pediatric field. 1. Pharmacokinetics of S-1108 was examined with 6 patients, at a dose of 4 mg/kg that was orally ingested 30 minutes after meal. Mean plasma concentrations at 30 minutes, 1, 2, 4, 6 and 8 hours after dose were 0.35, 0.63, 0.86, 0.75, 0.37 and 0.09 microgram/ml, respectively, with a half life of 1.14 hours. The urinary recovery rate in the first 8 hours was 25.5%. 2. The clinical efficacy of S-1108 was evaluated in 31 patients with various infectious diseases. S-1108 was administered at doses ranging 2 to 4.2 mg/kg/dosage, 3 times a day for 1/3 to 10 days. Clinical effects were excellent in 19, good in 12, with an efficacy rate of 100%. Bacteriologically, all causative organisms except two of Staphylococcus aureus and Haemophilus influenzae were eradicated, with an eradication rate of 80%. As an adverse reaction, mild diarrhea was noted in 2 patients. Slight elevations of GOT and/or GPT were noted in 2 patients. Only 1 child had difficulty ingesting the antibiotic preparation. From the above results, we have concluded that S-1108 is a highly effective and safe for patients with various infectious diseases in the pediatric fields.

[Fundamental and clinical studies on sisomicin in children (author's transl)].

Fundamental and clinical studies on sisomicin, a new aminoglycoside antibiotic were carried out and the following results were obtained. 1. Antibacterial activity of sisomicin was superior to that of gentamicin, amikacin, cefazolin and ampicillin against S. aureus and Ps. aeruginosa. Against E. coli and K. pneumoniae, it was superior to that of amikacin, cefazolin, ampicillin and equal or slightly superior to that of gentamicin. 2. Mean serum levels of sisomicin were 18.0 +/- 0.5 microgram/ml, 15.7 +/- 1.3 microgram/ml, 9.6 +/- 0.6 microgram/ml, 3.2 +/- 0.4 microgram/ml, 1.7 +/- 0.2 microgram/ml and 0.95 microgram/ml at 1/2, 1, 2, 4, 6 and 8 hours after a single intramuscular administration of sisomicin 2.0 mg/kg to 3 children. Mean half-life time was 1.6 +/- 0.2 hours. Mean urinary recovery was 60.4 +/- 7.5% within 6 hours after administration of sisomicin 1.6-2.1 mg/kg to 4 children. 3. Sisomicin was given intramuscularly to 13 children with acute pyelitis (11), acute cystitis (1) and stomatitis gangrenosa and cervical lymphadenitis (1). The daily dose was 2.0 -4.2 mg/kg, divided into twice. Clinical response was excellent in 8 and good in 5. In bacteriological examinations, 13 pathogens (E. coli 9, K. pneumoniae 2, Ps. aeruginosa 2) were eradicated after administration. No adverse reactions were observed.

[Studies of rokitamycin in pediatrics].

Pharmacokinetic, bacteriological and clinical studies on a new macrolide antibiotic, rokitamycin (RKM) dry syrup for pediatric use, were done, and results as summarized below were observed: 1. Five children with ages between 6 and 10 years were administered orally with RKM at a dose level of 10 mg/kg either at 30 minutes before or 30 minutes after meal on a crossover design, and plasma concentrations and urinary excretion rates of the drug were measured. Plasma concentrations of RKM following the administration before meal were 0.50 microgram/ml at 1/2 hour, 0.43 microgram/ml at 1 hour, 0.15 microgram/ml at 2 hours, 0.03 microgram/ml at 4 hours, and not detectable at 6 hours. Plasma concentrations following the administration after meal were 0.11 microgram/ml at 1/2 hour, 0.15 microgram/ml at 1 hour, 0.09 microgram/ml at 2 hours, 0.03 microgram/ml at 4 hours, and not detectable at 6 hours. The 0-6 hour urinary recovery rates were 1.41% following the administration before meal, and 0.93% following the administration after meal. These results suggested that the drug might be absorbed more rapidly, giving a higher plasma concentration, when administered before meal than when administered after meal. Changes in plasma concentrations of RKM following the administration of 10 mg/kg before meal were similar to those of two 100 mg RKM tablets (TMS-19-Q.GC tablets) to adult patients. Therefore, it seemed optimal to administer 10 mg/kg 3 times daily at fasting to children as a rule.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetic and clinical evaluations on ceftriaxone in neonates].

1. Ten neonates 0 to 28 days old (gestation: 37-42 weeks; birth weight: 2,160-3,640 g) received 20 mg/kg CTRX (8 cases) or 10 mg/kg (2 cases) by intravenous bolus injection, while 9 infants 35 days to 9 months old (gestation: 37-43 weeks; birth weight: 2,800-3,560 g) received 20 mg/kg by intravenous bolus injection, and their blood drug concentrations and urinary drug excretions were examined. Average blood levels of CTRX in the 20 mg/kg dosage group were 114 +/- 14.6 micrograms/ml at 30 minutes, 109 +/- 12.8 micrograms/ml at 1 hour, 100 +/- 12.6 micrograms/ml at 2 hours, 87.9 +/- 15.8 micrograms/ml at 4 hours, 72.8 +/- 15.3 micrograms/ml at 6 hours, and 50.1 +/- 12.3 micrograms/ml at 12 hours in the neonates; and 113 +/- 20.0 micrograms/ml at 30 minutes, 101 +/- 14.7 micrograms/ml at 1 hour, 83.6 +/- 9.3 micrograms/ml at 2 hours, 70.3 +/- 10.7 micrograms/ml at 4 hours, 56.9 +/- 8.6 micrograms/ml at 6 hours, and 35.7 +/- 9.2 micrograms/ml at 12 hours in the infants. Average half-lives of CTRX in blood were 10.3 +/- 4.5 hours in the neonates, and 6.6 +/- 1.9 hours in the infants. Average blood concentrations of CTRX in the 10 mg/kg dosage neonate group were 63.8 +/- 6.0 micrograms/ml at 30 minutes, 57.8 +/- 2.5 micrograms/ml at 1 hour, 53.5 +/- 0.7 micrograms/ml at 2 hours, 41.8 +/- 7.4 micrograms/ml at 4 hours, 32.4 +/- 5.9 micrograms/ml at 6 hours, and 20.8 +/- 1.1 micrograms/ml at 12 hours, and the half-life was 7.2 +/- 0.4 hours. These results suggest that blood concentrations are apparently dose-related in the neonate period; that the peak levels of the neonate and infant groups were similar (the levels at 30 minutes) not showing a relationship to age, gestation period or to birth weight; and that the higher the age was the shorter the half-life became with the half-life in the one week old group was 1.5 times as long as that in the older infant group. The half-life in the younger infant group, however, was similar to that in the older infant group. Urinary excretion was examined in 4 neonates and 2 infants. Average urinary recovery rates in 12 hours after intravenous injection were 40.8 +/- 8.3% in the neonate group and 44.8 +/- 12.8% in the infant group, showing that CTRX is excreted well even in the neonate period.(ABSTRACT TRUNCATED AT 400 WORDS)

[Basic and clinical studies on clarithromycin in pediatrics].

Clarithromycin (TE-031, A-56268) is a new macrolide antibiotic developed by Taisho Pharmaceutical Co., Ltd. Basic and clinical studies in the field of pediatrics were carried out on a granular preparation and 50 mg tablets of TE-031 designed for use in children. The following results were obtained. 1. Concentrations of TE-031 in the serum and its excretion in the urine were investigated in children. Six children were orally administered with a TE-031 granular preparation at 10 mg/kg in a cross-over study 30 minutes before meal and 30 minutes after meal. When the drug was ingested before meal, the mean peak serum concentration occurred 1 hour later and was 5.32 +/- 1.20 micrograms/ml. The mean half-life of TE-031 in the serum was 3.6 +/- 1.0 hours, and drug levels decreased to 1.94 +/- 0.55 micrograms/ml at 6 hours after dosing. In cases of the postprandial administration, the mean peak serum level was 4.21 +/- 1.25 micrograms/ml, occurring 2 hours after ingestion. The mean serum half-life in these cases was 3.5 +/- 1.3 hours, and serum levels decreased to 1.66 +/- 0.47 micrograms/ml at 6 hours after dosing. Mean urinary recovery rates during the initial 6 hours after ingestion were 30.5 +/- 6.4% in the cases of preprandial administration and 34.7 +/- 7.3% with postprandial administration. In addition, 30 minutes before meal, 50 mg tablets of TE-031 were orally administered to 3 children in a dose level equivalent to approximately 10 mg/kg, followed by monitoring of serum and urinary levels. It was found that the mean serum concentration showed a peak value of 4.10 +/- 0.44 micrograms/ml at 2 hours after dosing, the mean serum half-life was 3.5 +/- 0.7 hours, and the mean level fell to 1.90 +/- 0.55 micrograms/ml by 6 hours after dosing. The mean 6-hour urinary recovery rate was 32.7 +/- 12.1%. On the basis of the above results, it has been surmised that, in comparison to conventional macrolide antibiotics. TE-031 is better maintained in the blood at a high concentration and is more efficiently excreted into the urine. In addition, the data show that the bioavailability of TE-031 is slightly superior when the drug is administered on an empty stomach compared with after a meal. And finally, it was found that the granular and 50 mg tablet preparations of TE-031 are almost equivalent in terms of the absorption and the excretion of the drug.(ABSTRACT TRUNCATED AT 400 WORDS)

[Studies on sultamicillin in the field of pediatrics].

Pharmacokinetic and clinical studies on sultamicillin (SBTPC) were carried out in the field of pediatrics. 1. Absorption and excretion. A crossover study with a single oral administration of 10 mg/kg of SBTPC in fasting and after meal, and that with 10 mg/kg and 20 mg/kg of SBTPC after meal were carried out in 11 children (5-15 years) and in 6 children (8-15 years), respectively. Serum levels and urinary excretion of sulbactam (SBT) and ampicillin (ABPC) were determined. Mean serum concentrations of ABPC after oral administration of 10 mg/kg of SBTPC with in fasting or after meal, in the former study, peaked at 4.75 +/- 1.97 micrograms/ml in 1 hour and declined with a mean half-life of 0.81 +/- 0.18 hour and the mean serum concentration of ABPC at 6 hours after administration was 0.06 +/- 0.07 micrograms/ml. Mean serum concentration of ABPC study in the latter peaked at 2.95 +/- 0.79 micrograms/ml in 1 hour, and declined with a mean half-life of 1.35 +/- 0.43 hours, and the mean serum concentration of ABPC at 6 hours was 0.22 +/- 0.13 microgram/ml. Mean urinary recovery rates of ABPC in 6 hours after administration were 54.5 +/- 17.6% in the former study, and 63.2 +/- 14.3% in the latter. These results suggested a delay of absorption with meal. Mean serum concentrations of ABPC after oral administration of 10 mg/kg or 20 mg/kg of SBTPC after meal, in the former study, were 3.10 +/- 0.72 micrograms/ml at 1 hour and declined with a half-life of 1.22 +/- 0.32 hours, and those of ABPC were 0.22 +/- 0.12 microgram/ml at 6 hours, and they were 6.46 +/- 1.57 micrograms/ml, 1.48 +/- 0.51 hours and 0.55 +/- 0.40 microgram/ml, respectively in the latter study. Mean urinary recovery rates of ABPC in 6 hours, were 50.4 +/- 10.2% in the former study and 57.7 +/- 11.4%, in the latter. A dose response was observed with time course of mean serum concentrations. Mean serum concentrations of SBT were lower than those of ABPC, and they declined in a similar manner. The mean urinary recovery rate of SBT was similar or lower than that of ABPC. 2. Clinical study SBTPC was used for the treatment of a total of 38 pediatric patients with ages 6 months to 11 years and it's clinical effectiveness, bacteriological efficacy and adverse effects were evaluated.(ABSTRACT TRUNCATED AT 400 WORDS)

[Pharmacokinetic, bacteriological and clinical studies on imipenem/cilastatin sodium in neonates].

Pharmacokinetic, bacteriological and clinical studies on imipenem/cilastatin sodium (IPM/CS) were performed in neonates. The results obtained are summarized as follows. 1. Plasma levels and urinary excretion of IPM and CS sodium were determined in 7 neonates with ages between 7 and 26 days (gestation periods were 37 to 41 weeks and birth weights were 2,410 to 3,890 g) upon 1 hour drip intravenous infusion of IPM/CS at 10 mg/10 mg/kg, or 20 mg/20 mg/kg. Mean plasma concentrations of IPM reached their peaks at the end of infusion with levels of 12.7 +/- 3.0 micrograms/ml for the group given 10 mg/10 mg/kg, and 19.1 +/- 4.1 micrograms/ml for 20 mg/20 mg/kg. The concentration of IPM in plasma showed a dose-response to the 10 mg/10 mg/kg and 20 mg/20 mg/kg dosages. Concentrations decreased with half-lives of 1.87 +/- 0.71 hours and 1.97 +/- 0.21 hours for the low and the high dosages, and plasma levels at 8 hours after administration were 0.3 +/- 0.1 microgram/ml and 0.8 +/- 0.3 microgram/ml, respectively. Mean urinary recovery rates in 8 hours after administration were 37.6 +/- 11.8% and 26.8 +/- 17.2% for the low and the high dosages. While, mean plasma concentrations and mean urinary recovery rates of CS were higher than those of IPM, mean plasma half-lives of CS were similar to IPM. 2. IPM/CS was administered to 11 neonatal patients (with ages between 1 and 26 days) of various bacterial infections, and clinical effectiveness, bacteriological efficacy and adverse reactions were evaluated. Clinical efficacies in cases including 7 with acute pneumonia and 1 each with suspected septicemia, intrauterine infection, acute urinary tract infection and periproctal abscess were judged excellent in 10 and good in 1 case, and the efficacy rate was 100%. Causative organisms isolated from these patients included 3 strains of Escherichia coli and 1 strain each of Streptococcus pyogenes, Streptococcus agalactiae Enterococcus faecalis and Haemophilus influenzae. All the organisms were eradicated by IPM/CS, thus the bacteriological eradication rate was 100%. No adverse reactions were observed, but decreased platelet in 1 patient and increased GOT in 2 patients were found as abnormal laboratory test values. These changes, however were transient, and returned to normal after discontinuation of IPM/CS. It was concluded that the clinical results of IPM/CS are indicative of excellent efficacy, safety and usefulness of the drug in the treatment of infections in neonates.

[Laboratory and clinical evaluation of meropenem in pediatric field].

We performed laboratory and clinical evaluation of meropenem (SM-7338, MEPM), a new carbapenem antibiotics, in pediatric field. Pharmacokinetics of MEPM was examined with 5 patients, at a dose of 10 mg/kg via 30 minutes drip infusion. Mean plasma concentrations at 30 minutes, 1, 1.5, 2.5, 3.5 and 5.5 hours after dose were 18.8, 6.97, 3.62, 1.14, 0.43 and 0.12 micrograms/ml, respectively, with a half life of 0.96 hour. The urine recovery rate in 6 hours was 70.4%. Clinical efficacy of MEPM was evaluated in 36 patients with various infectious diseases. MEPM was administered at doses ranging 9.5 to 30.6 mg/kg/dosage, 3 to 4 times a day, 21/3 to 10 days. Clinical effects were excellent in 24, good in 11, fair in 1, with an efficacy rate of 97.2%. Bacteriologically, all causative organisms except one each of Haemophilus influenzae and Salmonella enteritidis were eradicated, an eradication rate for Gram-positive and Gram-negative bacteria were 100% and 93.3%, respectively. No side effects were observed. Elevations of GOT and/or GPT were noted in 2 patients. From the above results, we believe that MEPM is a highly effective and safe drug for patients with various infectious diseases in pediatric fields.

[Studies on panipenem/betamipron in the field of pediatrics].

Pharmacokinetic and clinical studies in pediatrics were performed on panipenem/betamipron (PAPM/BP), a combined drug of a carbapenem antibiotic (panipenem) and organic ion inhibitor (betamipron) at a weight ratio of 1:1. 1. Plasma levels and urinary excretion were studied when PAPM/BP, at 10 mg/10 mg/kg (4 cases) or 20 mg/20 mg/kg (5 cases), was administered using intravenous drip infusion in 30 minutes to 9 children (4-14 years old). The plasma PAPM level at the end of drip infusion was 30.75 +/- 4.98 micrograms/ml in the cases administered with 10 mg/10 mg/kg and 68.72 +/- 5.73 micrograms/ml in the cases administered with 20 mg/20 mg/kg. Drug concentrations then gradually decreased with half-lives of 1.08 +/- 0.09 hours and 0.98 +/- 0.02 hour, and reached 0.39 +/- 0.14 micrograms/ml and 0.62 +/- 0.06 micrograms/ml, respectively, after 5.5 hours. Plasma BP levels at the end of drip infusion was 18.93 +/- 3.75 micrograms/ml in the cases administered 10 mg/10 mg/kg and 37.09 +/- 2.68 micrograms/ml in the cases administered 20 mg/kg, and half-lives were 0.55 +/- 0.07 hour and 0.61 +/- 0.03 hour, respectively; the plasma BP level could not be determined in any cases after 5.5 hours. Mean urinary recovery rates of PAPM in the first 6 hours after the start of intravenous drip infusion were 33.0 +/- 6.1% in the cases administered 10 mg/10 mg/kg and 21.8 +/- 2.3% in the cases administered 20 mg/20 mg/kg and those of BP were 77.0 +/- 2.4% and 76.6 +/- 7.3%, respectively. 2. When PAPM/BP, was administered at 31.3 mg/31.3 mg/kg thought by intravenous drip infusion in 30 minutes to 1 case of purulent meningitis, PAPM levels were 0.76 micrograms/ml at the end of drip infusion but varied between 0.80 to 1.97 micrograms/ml 30 minutes after the end of drip infusion during 8 days of treatment. 3. PAPM/BP was administered to 43 cases, 47 diseases of bacterial infections in the domain of pediatrics to study its clinical efficacy, bacteriological efficacy and adverse reactions. Single doses were 5.2mg/5.2mg to 31.3 mg/31.3 mg/kg; frequencies of administration were 3 to 4 times a day, and durations of administration were 3 1/3 to 11 days; and total dosages ranged between 1.125 g/1.125 g and 11.0 g/11.0 g.(ABSTRACT TRUNCATED AT 400 WORDS)